# Drosophila and mouse models of PNPO deficiency

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $394,677

## Abstract

Abstract
 Pyridoxine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting inactive forms of Vitamin
B6 (VB6) in diet, including pyridoxine and pyridoxamine, to the only active form, pyridoxal 5'-phosphate (PLP).
PLP is a cofactor required for the syntheses of dopamine, serotonin and GABA in the brain.
 In humans, PNPO deficiency is known to cause neonatal epileptic encephalopathy (NEE). Mutations in
PNPO have been increasingly reported in NEE patients. Recent studies also identify PNPO as a contributor to
early-onset epilepsies and one of the16 epilepsy genes involved in the common epilepsies. However, due to
the lack of animal models, we know little about the developmental or adult functional impact of PNPO
deficiency at systems, circuit or cellular level (e.g. involvement of GABA, dopamine or serotonin synthesis)
under in vivo conditions. We know little about how mild PNPO deficiency interacts with other genetic defects or
environmental factors (e.g. VB6 in diet) to cause seizures or other conditions.
 We have identified the Drosophila homolog of PNPO and identified a Drosophila mutant (sgll95 flies) with
partial PNPO deficiency. Due to low PNPO activity, they are sensitive to dietary VB6 deficiency. We have since
generated global knock-down as well as knock-in models in which the endogenous wild-type (WT) fly PNPO
was replaced by human mutant PNPO found in patients. Viability during development, lifespan and seizure
phenotype of these flies depend on the specific genetic manipulation as well as availability of VB6 in diet. We
have also found that PNPO deficiency exacerbated other epileptic mutant alleles in flies with significant
synergistic interactions. In Aim 1, we will define specific developmental stages in fly models in which PNPO
deficiency leads to lethality and seizures. In Aim 2, we will define brain specific cell types involved in PNPO-
deficiency-induced lethality and seizures in fly and mouse models. We will test gene-gene interactions (e.g.,
PNPO and other known epilepsy genes). In Aim 3, we will generate and characterize fly and mouse models
that carry human PNPO mutations.
1

## Key facts

- **NIH application ID:** 10745949
- **Project number:** 5R01NS111122-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Xiaoxi Zhuang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $394,677
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745949

## Citation

> US National Institutes of Health, RePORTER application 10745949, Drosophila and mouse models of PNPO deficiency (5R01NS111122-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10745949. Licensed CC0.

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